The present invention is related to Cisplatin emulsion formulation with reduced toxicity, which is suitable for parenteral administration.
Cisplatin-cis-diamino-dichloroplatinum (CDDP) is a heavy metal complex containing a central atom of platinum surrounded by two chlorine atoms and two ammonium molecules in cis position. It is a potent anticancer drug used in the treatment of various solid tumors particularly of testes, ovaries and bladder. Cisplatin covalently binds to DNA bases and disrupts DNA function. Cisplatin is inactivated intracellularly and in the blood stream by sulfhydryl groups.
U.S. Pat. No. 4,302,446 (1981) and U.S. Pat. No. 4,322,391 (1982) patents describe preparation of cisplatin in microcrystalline form for ready solubility. U.S. Pat. No. 4,310,515 (1982) patent describes the method for preparing sterile aqueous solution of cisplatin. U.S. Pat. No. 4,915,956 (1990) patent also describes similar method for preparing sterile aqueous solution of cisplatin.
Cisplatin is highly toxic when administered as aqueous solution affecting kidneys, bone marrow and ears. Nephrotoxicity is the main dose limiting factor as 90% of cisplatin that is excreted from the body is removed from the kidney as a combination of glomerular filtration and tubular secretion (Physician Desk Reference 53rd edition: 1999).
Various attempts have been made to reduce the nephrotoxicity of the drug. These include adequate hydration and maintenance of urinary output before and for 24 hours after administration, I.V. Infusion of Amifostine at a dose of 910 mg/m2, 30 minutes prior to starting Cisplatin therapy. However these have been found inadequate.
Other attempts to minimise the nephrotoxicity of Cisplatin include combination chemotherapy, preparation of cisplatin analogues, entrapment of cisplatin in liposomes etc.
Cisplatin is difficult to entrap in liposomes efficiently because of its low aqueous solubility. Further it is difficult to stabilise the liposome preparation as it has been reported that Cisplatin is not retained in liposomal preparation during storage (Potkul, et. al. Am. J. Obstet. Gynecol. 164(2): 652-658; 1991. Gondal, et. al. Eur. J. Cancer 29A(11):1536-1542: 1993, Weiss, et. al. Drugs 46(3): 3660-377; 1993).
The main objective of the present invention is to develop a formulation of cisplatin that will be effective as an antineoplastic drug suitable for parenteral administration in human beings and other mammals but at the same time will not be as toxic as conventional aqueous solutions.
Accordingly, the present invention relates to a sterile pharmaceutical cisplatin composition as an oil-in-water emulsion having low toxicity for parenteral administration comprising
a) oily phase selected from group of vegetable oils, esters of medium or long chain fatty acids, fractionated or modified oil;
b) cisplatin (incorporated in oily phase);
c) emulsifiers such as natural phosphatides, modified phosphatides, synthetic non-ionic surfactants;
d) tonicity modifying agents selected from a group of compounds such as glycerin, mannitol, dextrose;
e) chelating agents selected from a group of compounds such as as edetates, desferrioxamine mesylate; and
f) water.
The process of making the above composition comprises dispersing Cisplatin in oily phase, preparing aqueous phase with tonicity modifying agent, chelating agent; adjusting pH to 8-11 and emulsifying the two phases after addition of emulsifying agent either to the aqueous phase or to the oily phase or to both phases; homogenising the emulsion to a particle size below 2 microns, keeping temperature of homogenised product below 25xc2x0 C.; filtering, filling in glass containers under nitrogen, sealing the filled containers and sterilising the sealed containers by autoclaving.
A composition of this invention comprises 0.005% to 0:5% by weight of Cisplatin, Preferably the composition comprises from 0.05 to 0.1% by weight of Cisplatin and more preferably about 0.05% or about 0.1% by weight of Cisplatin.
Cisplatin is dispersed in a oily phase prior to emulsification. Oily phase is present in an amount that is up to 30% by weight of the composition, preferably 5 to 25% and more preferably about 10% or about 20%. Typically the oily phase used is a vegetable oil and can be one or more of the vegetable oils such as soybean oil, sesame oil, cotton seed oil, safflower oil, sunflower oil, arachis oil, corn oil, castor oil or olive oil. Preferably the vegetable oil is soybean oil.
Alternatively the oily phase is an ester of medium or long chain fatty acids such as mono, di, or triglyceride or prepared material such as isopropyl myristate, isopropyl palmitate, ethyl oleate, a glycerol ester or polyoxyl hydrogenated castor oil. Oily phase can also include fractionated oil such as fractionated coconut oil or modified soybean oil. The composition of the present invention can also comprise a mixture of two or more of the above mentioned oily vehicles.
Cisplatin dispersed in an oily phase, is emulsified by means of emulsifier to give oil-in-water emulsion. Suitable emulsifiers include naturally occurring phosphatides and modified phosphatides. Naturally occurring phosphatides include egg phosphatide and soya phosphatides. Alternatively the emulsifier can be synthetic non-ionic surfactants such as ethoxylated ethers and esters and polyoxyethylene-polyoxypropylene co-polymers. Emulsifier used in the present invention may comprise a mixture of two or more of the above mentioned emulsifiers. Preferred emulsifiers arc egg and soya phosphatides.
The composition of the present invention is formulated suitably to exclude heavy metal contamination by using chelating agents. The chelating agents are selected from ethylenediaminetetraacetic acid (EDTA), derivatives of EDTA and desferrioxamine mesylate or a mixture thereof. Specifically the chelating agent used is disodium edeta.
The composition of the present invention is formulated suitably for the pH range to be at 6.0-8.5. pH is adjusted with an alkali such as sodium hydroxide or potassium hydroxide or a mixture thereof.
The composition of the present invention is made isotonic with blood by incorporation of a tonicity modifying agent such as glycerin, mannitol, dextrose, or a mixture thereof. Preferred tonicity modifying agent is glycerin.
The compositions of the present invention are specifically sterile oil-in-water emulsions and are prepared according to the conventional manufacturing procedures using aseptic techniques or terminal sterilisation by autoclaving.
In main embodiment of the invention, Cisplatin is dispersed in oily phase.
In another embodiment of the invention the type of emulsion prepared is oil-in-water type and Cisplatin is in oily phase.
In another embodiment of the invention, chelating agents are used in the emulsions to stabilise the emulsion, and prevent its discolouration.
In another embodiment of the invention, the homogenisation is done in repeated cycles to achieve less than 2 microns particle/globule size with intermediate cooling of the homogenised product to a temperature less than about 25xc2x0 C.
The composition of the present invention gives a product with reduced toxicity which is also suitable for parenteral use because of low particle size. Sterility, of the composition of the present invention is assured because the product is sterilised by end autoclaving. The composition of the present invention is easy to use as the product could be diluted with dextrose injection 5% or saline to get the required concentration for parenteral administration. The composition of the present invention also has a prolonged shelf life and hence suitable for a ready marketable product.